This research will explore the possibility that aminoglycosides bearing alkylating groups can offer a new approach to overcoming R-factor mediated bacterial resistance to aminoglycoside antibiotics. Alkylation of bacterial enzymes which inactivate aminoglycosides might inhibit them irreversibly and afford a synergistic effect to the actions of clinically important aminoglycosides. We will prepare and test against resistant strains of bacteria kanamycin B analogs with aziridine rings at the 2',3'-position (site of enzymatic phosphorylation by bacteria), the 2",3"-position (site of adenylation), and the 6'-position (site of acetylation). A 3',4'-epoxide analog will be synthesized. Semi-synthetic aminoglycosides in which the neamine unit is combined with monosaccharides not found naturally in aminoglycosides also will be explored. Emphasis will be placed on thiosugar analogs such as 4"-thioribostamycin and 4"-thiobutirosin. Kanamycin B analogs incorporating aminosugars such as daunosamine, desosamine, and mycosamine, which occur in other families of antibiotics will be synthesized and tested against aminoglycoside-resistant strains of bacteria.